Introduction

Uses for Zetia

Primary Hyperlipidemia and Mixed Dyslipidemia

Use alone or in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and non-HDL-cholesterol concentrations in the treatment of primary (heterozygous familial and nonfamilial) hyperlipidemia.120

Use in fixed combination with simvastatin as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hyperlipidemia or mixed dyslipidemia.20 In the IMPROVE-IT study, addition of ezetimibe to simvastatin therapy further reduced LDL cholesterol and improved cardiovascular outcomes in post-acute coronary syndrome (ACS) patients.309 In the SHARP study, fixed-combination preparation of simvastatin and ezetimibe reduced risk of major vascular and atherosclerotic events in patients with chronic kidney disease.20308

Use in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia.1 Effects on cardiovascular morbidity and mortality not established.1 Use with a fibric acid derivative other than fenofibrate not studied and currently not recommended.1 (See Specific Drugs under Interactions.)

Drug therapy is not a substitute for but an adjunct to nondrug therapies and measures (e.g., dietary management, weight control, physical activity, management of potentially contributory disease), which should be continued when drug therapy is initiated.91011

ACC/AHA cholesterol management guideline states that nonstatin drugs (e.g., ezetimibe) do not provide acceptable atherosclerotic cardiovascular disease (ASCVD) risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD.350 However, may be useful as adjuncts to statin therapy in high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations ≥190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly when evidence from randomized controlled studies suggest the nonstatin drug further reduces ASCVD events when added to statin therapy.350 Select nonstatin drug based on favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects and drug interactions) and patient preferences.350 Current recommendations from ACC/AHA regarding prevention of ASCVD and lifestyle modifications to reduce cardiovascular risk are available at [Web] or [Web]352

Homozygous Familial Hypercholesterolemia

Use in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available.120

Effects in patients currently undergoing LDL apheresis compared with those in patients not undergoing the procedure not established.4 Effects on clinical outcome and modification of other disease parameters (e.g., xanthoma formation, regression of atherosclerosis) not established.4

Homozygous Familial Hypercholesterolemia

Ezetimibe/simvastatin fixed combination (Vytorin): Ezetimibe 10 mg/simvastatin 40 mg once daily in the evening.20 Use as adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.20

Homozygous Familial Sitosterolemia

Prescribing Limits

Adults

Oral

Restrict use of ezetimibe 10 mg/simvastatin 80 mg dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects.20 In patients currently tolerating the ezetimibe 10 mg/simvastatin 80 mg daily dosage who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin), switch to alternative statin or statin-based regimen with less drug interaction potential.20

ACC/AHA cholesterol management guideline states it is reasonable to obtain baseline hepatic aminotransferase concentrations before initiating ezetimibe.350 When used with a statin, perform liver function tests at initiation of therapy and in accordance with the recommended monitoring schedule for the specific statin and as clinically indicated.1350 If ALT or AST concentrations increase to ≥3 times the ULN and are persistent, consider discontinuing ezetimibe and/or the statin.1

Musculoskeletal Effects

Marked (>10 times ULN) elevations of CK (CPK) reported.1 Elevations in CK concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.1

Myalgia, myopathy (i.e., unexplained muscle pain, tenderness, or weakness and CK concentration >10 times ULN), and/or rhabdomyolysis reported.112 Most cases of rhabdomyolysis occurred in patients receiving statin therapy prior to initiating ezetimibe; however, rhabdomyolysis also reported following ezetimibe monotherapy or following addition of ezetimibe to therapy with agents known to be associated with increased risk of rhabdomyolysis (e.g., fibric acid derivatives).120

Predisposing factors for the development of myopathy and/or rhabdomyolysis include increased dosages of statins, age >65 years, uncontrolled hypothyroidism, renal impairment, and potential statin-drug interactions.120 Immediately discontinue ezetimibe and any concomitant statin or fibric acid derivative (e.g., gemfibrozil, fenofibrate) if myopathy is diagnosed or suspected.112

General Precautions

Combination Therapy with Statins or Fenofibrate

When used in combination or fixed combination with a statin or fenofibrate, consult prescribing information of specific statin or fenofibrate for detailed information on usual cautions, precautions, and contraindications of these drugs.112

Risk of Cancer

Findings from the SEAS study suggested a possible increased risk of cancer with use of the fixed combination of simvastatin and ezetimibe.1517 The results of 2 large-scale randomized trials (SHARP and IMPROVE-IT) found no such association.307308309 FDA concluded that ezetimibe and the fixed-combination preparation of ezetimibe and simvastatin is not likely to increase the risk of cancer or cancer-related deaths.307

Specific Populations

Pregnancy

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use with caution in nursing women; not recommended unless potential benefits justify possible risks to infant.1

Pediatric Use

Safety and efficacy not established in children <10 years of age; use not recommended in these children.1

Safety and efficacy of ezetimibe alone or in fixed combination with simvastatin not established in prepubertal girls or in children ≤10 years of age.120

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.120

Use fixed combination of ezetimibe and simvastatin with caution, since age ≥65 years is a risk factor for myopathy, including rhabdomyolysis.20

Hepatic Impairment

Safety of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment currently not known; use not recommended in such patients.1

Renal Impairment

In patients with moderate to severe renal impairment receiving ezetimibe 10 mg/simvastatin 20 mg in fixed combination, incidence of certain adverse effects (serious effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo.120 Use higher dosages with caution and close monitoring in such patients, since renal impairment increases risk for myopathy.120 (See Renal Impairment under Dosage and Administration.)

Adverse effects associated with combination therapy generally similar to those reported with monotherapy.1 However, elevations in transaminase concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.1

When used in fixed combination with simvastatin, consider drug interactions associated with simvastatin.12 No formal drug interaction studies to date with fixed-combination preparation other than that with extended-release niacin.20 (See Specific Drugs under Interactions.)

Pharmacokinetic and pharmacologic interaction unlikely based on one study;1812 no effect on R- or S-warfarin exposure1

Increased INR with combined ezetimibe-warfarin therapy reported during postmarketing experience; most patients also on other drugs112

Monitor INR appropriately if ezetimibe is initiated in a patient receiving warfarin1

Zetia Pharmacokinetics

Absorption

Bioavailability

Approximately 93% of dose is absorbed systemically following oral administration.1

Absolute bioavailability cannot be determined because ezetimibe is virtually insoluble in aqueous media suitable for injection.1 Ezetimibe/simvastatin fixed-combination preparation is bioequivalent to corresponding dosages of the individual components.12

Food

Special Populations

Increased plasma concentrations in geriatric individuals (≥65 years of age), in patients with hepatic impairment, and in patients with severe renal impairment.1 (See Special Populations under Dosage and Administration.)

No differences in pharmacokinetic parameters between blacks and Caucasians.1 Studies in Asian individuals indicated similar pharmacokinetics as observed in Caucasian individuals.1

Distribution

Plasma Protein Binding

Elimination

Metabolism

Rapidly metabolized principally in small intestine and liver to ezetimibe glucuronide (active).1 Ezetimibe and ezetimibe glucuronide constitute approximately 10–20% and 80–90%, respectively, of total drug in plasma.1

Elimination Route

Excreted in feces (78%) and urine (11%) within 10 days after dosing.1 Major component in feces is ezetimibe (69% of administered dose); major component in urine is ezetimibe glucuronide (9% of administered dose).1

Actions

Localizes at brush border of small intestine and inhibits absorption of cholesterol,348 resulting in decreased delivery of intestinal cholesterol to liver.1 Intestinal absorption of cholesterol reduced by approximately 54% in a limited number of patients with hypercholesterolemia.16

Has been shown to reduce concentrations of noncholesterol sterols,8 including sitosterol and campesterol.16

Does not appear to inhibit hepatic cholesterol synthesis or increase bile acid excretion.1 Does not appear to inhibit absorption of triglycerides, fatty acids, bile acids, progesterone, or ethyl estradiol.1 No clinically relevant effects on plasma concentrations of fat-soluble vitamins A, D, and E;8 does not appear to impair adrenocortical steroid production.1

Cholesterol-lowering effects of ezetimibe and statins or of ezetimibe and fenofibrate are additive.1

Advice to Patients

Importance of adherence to prescribed directions for use, particularly when used concomitantly with other antilipemic agents.112

Risk of myopathy and/or rhabdomyolysis; risk increased when used concomitantly with certain other drugs or grapefruit juice.120 Importance of promptly informing clinicians of unexplained muscle pain, weakness, or tenderness, particularly if accompanied by malaise or fever or if such manifestations persist after discontinuance of therapy.120

Risk of adverse hepatic effects.120 Importance of monitoring liver function tests at initiation of ezetimibe if used in combination with a statin and thereafter in accordance with the recommendation of the statin.120 Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice) when ezetimibe is used in combination simvastatin.20

Importance of women informing their clinician if they are or plan to become pregnant.120 Importance of advising women and adolescent girls to avoid pregnancy (i.e., using effective and appropriate contraceptive methods) and informing pregnant women of risk to fetus when using ezetimibe in combination with statin therapy.120

Importance of avoiding breast-feeding when using ezetimibe in combination with statin therapy.120 If the patient has a lipid disorder and is breast-feeding, importance of contacting a clinician to discuss other antilipemic treatment options.120

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.112

Importance of informing patients of other important precautionary information.112 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015-23.

10. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda, MD: National Institutes of Health. (NIH publication No. 01-3670.)

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Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. Data sources include IBM Watson Micromedex (updated 1 May 2019), Cerner Multum™ (updated 2 May 2019), Wolters Kluwer™ (updated 1 May 2019) and others.